Insulin resistance is a sine qua non of Type 2 diabetes and a frequent complication of obesity, lipodystrophy, inflammation, steroid use, critical illness, and a variety of other conditions and insults. It has long been a mystery how so many profoundly different stimuli all result in the same clinical phenotype. Furthermore, most studies of insulin resistance have posited the action of cytoplasmic, mitochondrial, and ER-related pathways, such as toxic lipid intermediates, oxidative stress, or ER stress. Very few studies have focused on nuclear mechanisms of insulin resistance, despite strong evidence that transcriptional and epigenetic factors must be in play. We have used a comparative model of insulin resistance in 3T3-L1 adipocytes treated with dexamethasone (Dex) or TNF? (TNF) to identify novel pathways that cause this disorder. Integrated transcriptional, epigenomic, and computational analysis have identified two nuclear hormone receptors as important; TNF-mediated glucocorticoid receptor (GR) action and the vitamin D receptor (VDR). This proposal will identify the mechanisms by which the GR and VDR promote insulin resistance in both murine and human cells, and will identify the specific gene targets that mediate this effect. Importantly, it will also validate our findings in vivo, using both gain- and loss-of-function approaches. Taken together, this proposal has the potential to characterize two novel pathways of insulin resistance with inherent therapeutic potential.